Cell Type-specific Circuit Mechanisms of Absence Epilepsy
Abstract number :
1.016
Submission category :
1. Basic Mechanisms / 1B. Epileptogenesis of genetic epilepsies
Year :
2023
Submission ID :
133
Source :
www.aesnet.org
Presentation date :
12/2/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Xiaolong Jiang, Ph.D – Baylor College of Medicine
Atul Maheshwari, M.D. – Associate professor, Department of Neurology, Baylor College of Medicine; Qinglong Miao, Ph.D – Instructor, Department of Neurology, Baylor College of Medicine; Jeffrey Noebels,, M.D., Ph.D. – Professor, Department of Neurology, Baylor College of Medicine; Siyuan Song, Ph.D. – postdoc, Department of Neuroscience, Baylor College of Medicine
Rationale: Absence seizure is a special type of epilepsy in children featured by generalized spike-wave (SW) electroencephalography (EEG) change. While earlier studies attribute the origin of SW discharges of absence seizure to the thalamus, there is now growing evidence that the cortex exerts a more prominent role in the generation and expression of SW activity, and their focal onset zone may reside in the somatosensory cortex (S1). To provide more insight into the minimal circuit elements necessary for the induction of SW discharge, we take advantage of a monogenic mouse model of absence epilepsy, stargazer, to examine what circuit defect may be specifically developed in the S1 as a result of mutations in Cacng2, a gene encoding an AMPA receptor trafficking protein stargazin (stg).
Methods: Whole-cell patch clamp recording was used to examine spontaneous excitatory postsynaptic currents (sEPSCs) of both excitatory and inhibitory neurons in somatosensory cortex (S1) across the layers from homozygous stg (stg/stg) mutant mice and then compared to their wildtype littermates. Simultaneous eight-cell patch recordings were performed on S1 neurons across the layers to examine cell-type specific connectivity change in stg/stg to further dissect the specific cell types and pathways impacted by the genetic lesions. In addition, single-cell RNA-sequencing and chemogenetic approach were used to manipulate specific cell type to establish the causative relationship between circuit deficits and seizure generation.
Results: Our pan-circuit mapping pinpointed a dormant state of deep layer PV+ interneurons in S1 as a result of the disruption of excitatory drive to these interneurons in stg. This layer- and cell type-specific defect is consistent with the restriction of Cacng2 expression to deep layer PV+ interneurons, and thus is primary and occurs independently of seizure stages. In contrast, the connectivity changes of SST+ interneurons in stg were secondary and occurred only when seizures manifested in this model. Chemogenetic activation of deep layer PV+ interneurons abolished absence seizures in stg.
Conclusions: Our data support that dormant PV+ interneurons in deep layers is an essential circuit basis for absence seizures in stargazer.
Funding: R01 NS110767
Basic Mechanisms